Association of timing and agent for venous thromboembolism prophylaxis in patients with severe traumatic brain injury on venous thromboembolism events, mortality, neurosurgical intervention, and discharge disposition.

BACKGROUND: Trauma patients are at increased risk for venous thromboembolism events (VTEs). The decision of when to initiate VTE chemoprophylaxis (VTEP) and with what agent remains controversial in patients with severe traumatic brain injury (TBI). METHODS: This comparative effectiveness study evaluated the impact of timing and agent for VTEP on outcomes for patients with severe TBI (Abbreviated Injury Scale head score of 3, 4, or 5). Data were collected at 35 Level 1 and 2 trauma centers from January 1, 2017, to June 1, 2022. Patients were placed into analysis cohorts: no VTEP, low-molecular-weight heparin (LMWH) ≤48 hours, LMWH >48 hours, heparin ≤48 hours, and heparin >48 hours. Propensity score matching accounting for patient factors and injury characteristics was used with logistic regression modeling to evaluate in-hospital mortality, VTEs, and discharge disposition. Neurosurgical intervention after initiation of VTEP was used to evaluate extension of intracranial hemorrhage. RESULTS: Of 12,879 patients, 32% had no VTEP, 36% had LMWH, and 32% had heparin. Overall mortality was 8.3% and lowest among patients receiving LMWH ≤48 hours (4.1%). Venous thromboembolism event rates were lower with use of LMWH (1.6% vs. 4.5%; odds ratio, 2.98; 95% confidence interval, 1.40-6.34; p = 0.005) without increasing mortality or neurosurgical interventions. Venous thromboembolism event rates were lower with early prophylaxis (2.0% vs. 3.5%; odds ratio, 1.76; 95% confidence interval, 1.15-2.71; p = 0.01) without increasing mortality ( p = 1.0). Early VTEP was associated with more nonfatal intracranial operations ( p < 0.001). However, patients undergoing neurosurgical intervention after VTEP initiation had no difference in rates of mortality, withdrawal of care, or unfavorable discharge disposition ( p = 0.7, p = 0.1, p = 0.5). CONCLUSION: In patients with severe TBI, LMWH usage was associated with lower VTE incidence without increasing mortality or neurosurgical interventions. Initiation of VTEP ≤48 hours decreased VTE incidence and increased nonfatal neurosurgical interventions without affecting mortality. Low-molecular-weight heparin is the preferred VTEP agent for severe TBI, and initiation ≤48 hours should be considered in relation to these risks and benefits. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

A multicenter study of DDAVP versus platelet transfusions for antiplatelet agent reversal in patients with traumatic brain injury.

BACKGROUND: Antiplatelet agents have been shown to worsen outcomes following traumatic injury. Research on desmopressin (DDAVP) and platelet transfusion for antiplatelet reversal is limited. We aimed to evaluate the effect of these agents on patients taking pre-injury antiplatelet medications who experienced traumatic brain injury (TBI) after blunt trauma. METHODS: This is a retrospective cohort study of adult trauma patients from 2014 to 2021 on aspirin and/or a P2Y12 inhibitor. Patients were stratified into groups based on if they received DDAVP, platelets, both agents, or neither. RESULTS: Of 5525 included patients, 4696 (85.4%) were not reversed, 461 (8.4%) received platelets, 173 (3.1%) received DDAVP, and 172 (3.1%) received both reversals. There was no statistically significant difference in length of stay between, but patients who received platelets or both reversals were more likely to have hospital complications (p < 0.05), longer hospital length of stay (p < 0.001), and longer ICU length of stay (p < 0.001) compared to those who did not receive reversal. A subgroup analysis of patients with a head AIS of 4 or 5 confirmed these findings. CONCLUSIONS: Patients who received platelets or both reversals had a longer length of hospital stay and length of ICU stay. It is difficult to recommend one treatment over another based on our results alone. Further studies are needed to help clarify the risks and benefits of reversal agents in this patient population.

Four-factor prothrombin complex concentrate versus andexanet alfa for the reversal of traumatic brain injuries.

BACKGROUND: Andexanet alfa was approved in 2018 for reversal of direct oral anticoagulants but due to issues of cost and access, four-factor prothrombin complex concentrate (4F-PCC) continues to be used for this indication. The objective of this study is to evaluate outcomes of reversal with these agents in patients with isolated traumatic brain injuries (TBI). METHODS: This is a retrospective review of 35 trauma centres from 2014 to 2021. Patients were included with an Abbreviated Injury Scale (AIS)>2 for head and having received andexanet alfa or 4F-PCC within 24 hours of admission. Patients were excluded if P2Y12 inhibitor use or AIS>2 outside of head. Primary outcome includes rate of mortality/hospice at hospital discharge. Secondary outcomes include a composite of serious hospital complications. A subgroup analysis of severe TBI patients (AIS head 4 or 5) was completed. Multivariable logistic regression was used to account for differences in comorbidities and TBI severity. RESULTS: 4F-PCC was given to 265 patients with another 59 receiving andexanet alfa. Patients in the andexanet alfa group were more likely to have an AIS head score of 5 (47.5% vs 26.1%; p<0.005). After adjusting for severity of TBI and comorbidities with regard to tomortality/hospice, there were 15 (25.4%) patients in the andexanet alfa group and 49 (18.5%) in the 4F-PCC group (OR 1.34; 95% CI 0.67 to 2.71). This remained consistent when looking at severe patients with TBI with 12 (28.6%) andexanet alfa patients and 37 (28.7%) 4F-PCC patients (OR 0.93 (95% CI 0.40 to 2.16)). Severe hospital complications were also similar between groups with 5 (8.5%) andexanet alfa patients as compared with 21 (7.9%) 4F-PCC patients (OR 1.01; 95% CI 0.36 to 2.88). CONCLUSION: There was no firm conclusion on the treatment effect in mortality/hospice or serious complications among isolated TBI patients reversed with 4F-PCC as compared with andexanet alfa.

Is reversal of anticoagulants necessary in neurologically intact traumatic intracranial hemorrhage?

INTRODUCTION: Falls are the leading cause of injury in older individuals, with intracranial hemorrhage (ICH) being a common complication. Anticoagulants, such as vitamin K antagonist and direct oral anticoagulants, are increasingly utilized, and clinicians may question the necessity of reversal in patients with minor ICH, especially in the setting of increased risk of adverse events. This study aimed to identify a population of patients with minor traumatic ICH at low risk for poor-neurologic status where anticoagulant reversal may not improve outcomes. METHODS: This retrospective cohort study utilized data accessed from 35 trauma centers from 2018 to 2021. Patients included had a preinjury anticoagulant regimen, ICH due to blunt trauma, Glasgow Coma Scale score of 15, an Abbreviated Injury Scale (AIS) head score from 2 to 4, and an AIS of ≤1 for non-head regions within 24 h of hospital arrival. Patients were excluded if they required an emergent neurosurgical procedure or were on a preinjury purinergic-P2 receptor-12 protein (P2Y12) inhibitor. The primary outcome was the rate of in-hospital mortality or hospice. RESULTS: There were 654 patients on preinjury anticoagulation who were included with a minor traumatic ICH without neurologic deficits. Overall, 263 patients were reversed and 391 were not reversed. Twelve (4.6%) patients with in-hospital mortality or hospice were reversed compared with 19 (4.91%) patients who were not reversed (p = 0.861). A composite of hospital complications occurred in 21 (8%) reversed patients and 34 (8.7%) not reversed patients (p = 0.748). The average intensive care unit length of stay was 1.4 ± 3.4 days in the reversed group and 1.1 ± 1.8 days in the not reversed group (p = 0.069). CONCLUSION: This study found no difference in hospital outcomes between patients with minor traumatic ICH on oral anticoagulants who were neurologically intact that were reversed versus those who were not reversed. Further studies should continue to define the subset of traumatic ICH patients who may not require reversal of anticoagulation.

Reusing personal protective equipment (PPE) did not increase surgical site infection in trauma surgical patients during the COVID-19 pandemic: A retrospective cohort study in Michigan Trauma Centers.

BACKGROUND: Reuse of personal protective equipment (PPE), masks more specifically, during the COVID-19 pandemic was common. The primary objective of this study was to compare pre-pandemic surgical site infection (SSI) rates prior to reuse of PPE, to pandemic SSI rates after reuse of PPE in trauma surgical patients. METHODS: A retrospective cohort analysis collected from the Michigan Trauma Quality Improvement Program database was performed. The pre-COVID cohort was from March 1, 2019 to December 31, 2019 and post-COVID cohort was March 1, 2020 to December 31,2020. Descriptive statistics were used to assess differences between variables in each cohort. RESULTS: Nearly half (49.8%) of our cohort (n = 48,987) was in the post-COVID group. There was no significant difference in frequency of operative intervention between groups (p > .05). There was no significant increase (p > .05) between pre- and post-COVID cohorts for superficial, deep, or organ space SSI when reuse of masks was common. CONCLUSION: Reuse of PPE did not lead to an increase in SSI in surgical patients. These findings are consistent with previous studies, but the first to be described in the trauma surgical patient population. Studies such as this may help inform further discussion regarding PPE usage as we continue to emerge from the current pandemic with the continuous threat of future pandemics.

Research on neonatal microbiomes: what neonatologists need to know.

The aim of this article is to educate neonatal caregivers about metagenomics. This scientific field uses novel and ever changing molecular methods to identify how infants become colonized with microbes after birth. Publications using metagenomics appear infrequently in the neonatal literature because clinicians are unaccustomed to the analytical techniques, data interpretation, and illustration of the results. This review covers those areas. After a brief introduction of neonatal citations forthcoming from metagenomic studies, the following topics are covered: (1) the history of metagenomics, (2) a description of current and emerging instruments used to define microbial populations in human organs, and (3) how extensive databases generated by genome analyzers are examined and presented to readers. Clinicians may feel like they are learning a new language; however, they will appreciate this task is essential to understanding and practicing neonatal medicine in the future.

Virtual screening for R-groups, including predicted pIC50 contributions, within large structural databases, using Topomer CoMFA.

Multiple R-groups (monovalent fragments) are implicitly accessible within most of the molecular structures that populate large structural databases. R-group searching would desirably consider pIC50 contribution forecasts as well as ligand similarities or docking scores. However, R-group searching, with or without pIC50 forecasts, is currently not practical. The most prevalent and reliable source of pIC50 predictions, existing 3D-QSAR approaches, is also difficult and somewhat subjective. Yet in 25 of 25 trials on data sets on which a field-based 3D-QSAR treatment had already succeeded, substitution of objective (canonically generated) topomer poses for the original structure-guided manual alignments produced acceptable 3D-QSAR models, on average having almost equivalent statistical quality to the published models, and with negligible effort. Their overall pIC50 prediction error is 0.805, calculated as the average over these 25 topomer CoMFA models in the standard deviations of pIC50 predictions, derived from the 1109 possible "leave-out-one-R-group" (LOORG) pIC50 contributions. (This novel LOORG protocol provides a more realistic and stringent test of prediction accuracy than the customary "leave-out-one-compound" LOO approach.) The associated average predictive r(2) of 0.495 indicates a pIC50 prediction accuracy roughly halfway between perfect and useless. To assess the ability of topomer-CoMFA based virtual screening to identify "highly active" R-groups, a Receiver Operating Curve (ROC) approach was adopted. Using, as the binary criterion for a "highly active" R-group, a predicted pIC50 greater than the top 25% of the observed pIC50 range, the ROC area averaged across the 25 topomer CoMFA models is 0.729. Conventionally interpreted, the odds that a "highly active" R-group will indeed confer such a high pIC50 are 0.729/(1-0.729) or almost 3 to 1. To confirm that virtual screening within large collections of realized structures would provide a useful quantity and variety of R-group suggestions, combining shape similarity with the "highly active" pIC50, the 50 searches provided by these 25 models were applied to 2.2 million structurally distinct R-group candidates among 2.0 million structures within a ZINC database, identifying an average of 5705 R-groups per search, with the highest predicted pIC50 combination averaging 1.6 log units greater than the highest reported pIC50s.

Acute molecular markers of rodent hepatic carcinogenesis identified by transcription profiling.

Currently, the only way to identify nongenotoxic hepatocarcinogens is through long-term repeat dose studies such as the 2 year rodent carcinogenicity assay. Such assays are both time consuming and expensive and require large amounts of active pharmaceutical or chemical ingredients. Thus, the results of the 2 year assay are not known until very late in the discovery and development process for new pharmaceutical entities. Although in many cases nongenotoxic carcinogenicity in rodents is considered to be irrelevant for humans, a positive finding in a 2 year carcinogenicity assay may increase the number of studies to demonstrate the lack of relevance to humans, delay final submission and subsequent registration of a product, and may result in a "black box" carcinogenicity warning on the label. To develop early identifiers of carcinogenicity, we applied transcription profiling using several prototype rodent genotoxic and nongenotoxic carcinogens, as well as two noncarcinogenic hepatotoxicants, in a 5 day repeat dose in vivo toxicology study. Fluorescent-labeled probes generated from liver mRNA prepared from male Sprague-Dawley rats treated with one of three dose levels of bemitradine, clofibrate, doxylamine, methapyrilene, phenobarbital, tamoxifen, 2-acetylaminofluorene, 4-acetylaminofluorene, or isoniazid were hybridized against rat cDNA microarrays. Correlation of the resulting data with an estimated carcinogenic potential of each compound and dose level identified several candidate molecular markers of rodent nongenotoxic carcinogenicity, including transforming growth factor-beta stimulated clone 22 and NAD(P)H cytochrome P450 oxidoreductase.